Restless legs syndrome

For the song "Restless Legs" by Half Man Half Biscuit, see Achtung Bono.
Restless legs syndrome
Willis-Ekbom disease (WED),[1] Wittmaack-Ekbom syndrome

Sleep pattern of a person with restless legs syndrome (red) versus a healthy sleep pattern (blue).
Classification and external resources
Specialty Sleep medicine
ICD-10 G25.8
ICD-9-CM 333.94
OMIM 102300 608831
DiseasesDB 29476
MedlinePlus 000807
eMedicine neuro/509
Patient UK Restless legs syndrome
MeSH D012148

Restless legs syndrome (RLS) is a disorder that causes a strong urge to move one's legs.[2] There is often an unpleasant feeling in the legs that improves somewhat with moving them. Occasionally the arms may also be affected. The feelings generally happen when at rest and therefore can make it hard to sleep. Due to the disturbance in sleep people with RLS may have daytime sleepiness, low energy, irritability, and a depressed mood.[2] Additionally, many have limb twitching during sleep.[3]

Risk factors for RLS include low iron levels, kidney failure, Parkinson disease, diabetes, rheumatoid arthritis, and pregnancy.[2][4] A number of medications may also trigger the disorder including antidepressants, antipsychotics, antihistamines, and calcium channel blockers.[5] There are two main types. One is early onset RLS which starts before age 45, runs in families and worsens over time. The other is late onset RLS which begins after age 45, starts suddenly, and does not worsen.[2] Diagnosis is generally based on a person's symptoms after ruling out other potential causes.[6]

Restless leg syndrome may resolve if the underlying problem is addressed.[7] Otherwise treatment includes lifestyle changes and medication.[2] Lifestyle changes that may help include stopping alcohol and tobacco, and sleep hygiene.[7] Medications used include levodopa or a dopamine agonist such as pramipexole. RLS affects an estimated 2.5–15% of the American population.[4] Females are more commonly affected than males and it becomes more common with age.[8]

Signs and symptoms

RLS sensations range from pain or an aching in the muscles, to "an itch you can't scratch", a "buzzing sensation", an unpleasant "tickle that won't stop", a "crawling" feeling, or limbs jerking while awake. The sensations typically begin or intensify during quiet wakefulness, such as when relaxing, reading, studying, or trying to sleep.[9]

It is a "spectrum" disease with some people experiencing only a minor annoyance and others having major disruption of sleep and impairments in quality of life.[10]

The sensations—and the need to move—may return immediately after ceasing movement or at a later time. RLS may start at any age, including childhood, and is a progressive disease for some, while the symptoms may remit in others.[11] In a survey among members of the Restless Legs Syndrome Foundation,[12] it was found that up to 45% of patients had their first symptoms before the age of 20 years.[13]

The sensations are unusual and unlike other common sensations. Those with RLS have a hard time describing them, using words like: uncomfortable, painful, 'antsy', electrical, creeping, itching, pins and needles, pulling, crawling, buzzing, and numbness. It is sometimes described similar to a limb 'falling asleep' or an exaggerated sense of positional awareness of the affected area. The sensation and the urge can occur in any body part; the most cited location is legs, followed by arms. Some people have little or no sensation, yet still have a strong urge to move.
Movement usually brings immediate relief, although temporary and partial. Walking is most common; however, stretching, yoga, biking, or other physical activity may relieve the symptoms. Continuous, fast up-and-down movements of the leg, and/or rapidly moving the legs toward then away from each other, may keep sensations at bay without having to walk. Specific movements may be unique to each person.
Sitting or lying down (reading, plane ride, watching TV) can trigger the sensations and urge to move. Severity depends on the severity of the person's RLS, the degree of restfulness, duration of the inactivity, etc.
Some experience RLS only at bedtime, while others experience it throughout the day and night. Most people experience the worst symptoms in the evening and the least in the morning.
These symptoms of RLS can make sleeping difficult for many patients and a recent poll shows the presence of significant daytime difficulties resulting from this condition. These problems range from being late for work to missing work or events because of drowsiness. Patients with RLS who responded reported driving while drowsy more than patients without RLS. These daytime difficulties can translate into safety, social and economic issues for the patient and for society.

Individuals with RLS have higher rates of depression and anxiety disorders.[14]

Primary and secondary

RLS is categorized as either primary or secondary.

Causes

RLS is often due to iron deficiency (low total body iron status) and this accounts for 20% of cases.[15] A study published in 2007 noted that RLS features were observed in 34% of people having iron deficiency as against 6% of controls.[16]

Other associated conditions include varicose vein or venous reflux, folate deficiency, magnesium deficiency, fibromyalgia, sleep apnea, uremia, diabetes, thyroid disease, peripheral neuropathy, Parkinson's disease, POTS, and certain autoimmune diseases such as Sjögren's syndrome, celiac disease, and rheumatoid arthritis. RLS can also worsen in pregnancy.[17] In a 2007 study, RLS was detected in 36% of people attending a phlebology (vein disease) clinic, compared to 18% in a control group.[18]

ADHD

An association has been observed between attention deficit hyperactivity disorder (ADHD) and RLS or periodic limb movement disorder. Both conditions appear to have links to dysfunctions related to the neurotransmitter dopamine, and common medications for both conditions among other systems, affect dopamine levels in the brain.[19] A 2005 study suggested that up to 44% of people with ADHD had comorbid (i.e. coexisting) RLS, and up to 26% of people with RLS had confirmed ADHD or symptoms of the condition.[20] A 2009 study updated this to report that 39% of people with RLS also might have ADHD compared to 14% of controls and that those showing signs of both had more severe RLS, suggesting that perhaps either the difficulties of RLS and low sleep quality caused ADHD-like distraction or that dopamine was a possible common factor and its improvement helped both, and that people with RLS might wish to consider ADHD testing as well, but cautioned that neither condition was proven as the cause of the other.

Medications

Certain medications may cause or worsen RLS, or cause it secondarily, including:

Both primary and secondary RLS can be worsened by surgery of any kind; however, back surgery or injury can be associated with causing RLS.[25]

The cause vs. effect of certain conditions and behaviors observed in some patients (ex. excess weight, lack of exercise, depression or other mental illnesses) is not well established. Loss of sleep due to RLS could cause the conditions, or medication used to treat a condition could cause RLS.[26][27]

Genetics

More than 60% of cases of RLS are familial and are inherited in an autosomal dominant fashion with variable penetrance.[28]

Research and brain autopsies have implicated both dopaminergic system and iron insufficiency in the substantia nigra.[29] Iron is well-understood to be an essential co-factor for the formation of L-dopa, the precursor of dopamine.

Six genetic loci found by linkage are known and listed below. Other than the first one, all of the linkage loci were discovered using an autosomal dominant model of inheritance.

  1. The first genetic locus was discovered in one large French Canadian family and maps on chromosome 12q.[30][31] This locus was discovered using an autosomal recessive inheritance model. Evidence for this locus was also found using a transmission disequilibrium test (TDT) in 12 Bavarian families.[32]
  2. The second RLS locus maps to chromosome 14q and was discovered in one Italian family.[33] Evidence for this locus was found in one French Canadian family.[34] Also, an association study in a large sample 159 trios of European descent showed some evidence for this locus.[35]
  3. This locus maps to chromosome 9p and was discovered in two unrelated American families.[36] Evidence for this locus was also found by the TDT in a large Bavarian family,[37] in which significant linkage to this locus was found.[38]
  4. This locus maps to chromosome 20p and was discovered in a large French Canadian family with RLS.[39]
  5. This locus maps to chromosome 2p and was found in three related families from population isolated in South Tyrol.[40]
  6. The sixth locus is located on chromosome 16p12.1 and was discovered by Levchenko et al. in 2008.[41]

Three genes, MEIS1, BTBD9 and MAP2K5, were found to be associated to RLS.[42] Their role in RLS pathogenesis is still unclear. More recently, a fourth gene, PTPRD was found to be associated to RLS[43]

There is also some evidence that periodic limb movements in sleep (PLMS) are associated with BTBD9 on chromosome 6p21.2,[44][45] MEIS1, MAP2K5/SKOR1, and PTPRD.[45] The presence of a positive family history suggests that there may be a genetic involvement in the etiology of RLS.

Mechanism

Most research on the disease mechanism of restless legs syndrome has focused on the dopamine and iron system.[46][47] These hypotheses are based on the observation that iron and levodopa, a prodrug of dopamine that can cross the blood–brain barrier and is metabolized in the brain into dopamine (as well as other mono-amine neurotransmitters of the catecholamine class) can be used to treat RLS, levodopa being a medicine for treating hypodopaminergic (low dopamine) conditions such as Parkinson's disease, and also on findings from functional brain imaging (such as positron emission tomography and functional magnetic resonance imaging), autopsy series and animal experiments.[48] Differences in dopamine- and iron-related markers have also been demonstrated in the cerebrospinal fluid of individuals with RLS.[49] A connection between these two systems is demonstrated by the finding of low iron levels in the substantia nigra of RLS patients, although other areas may also be involved.[50]

Diagnosis

There are no specific tests for RLS, but non-specific laboratory tests are used to rule out other causes such as vitamin deficiencies. According to the National Institutes of Health's National Institute of Neurological Disorders and Stroke, four symptoms are used to confirm the diagnosis:[51]

NIH criteria

In 2003, a US National Institutes of Health (NIH) panel modified their criteria to include the following:

  1. An urge to move the limbs with or without sensations.
  2. Improvement with activity. Many patients find relief when moving and the relief continues while they are moving. In more severe RLS this relief of symptoms may not be complete or the symptoms may reappear when the movement ceases.
  3. Worsening at rest. Patients may describe being the most affected when sitting for a long period of time, such as when traveling in a car or airplane, attending a meeting, or watching a performance. An increased level of mental awareness may help reduce these symptoms.
  4. Worsening in the evening or night.[9] Patients with mild or moderate RLS show a clear circadian rhythm to their symptoms, with an increase in sensory symptoms and restlessness in the evening and into the night.

Differential diagnosis

Other conditions that can produce similar symptoms include: akathisia and nocturnal leg cramps.

Peripheral artery disease and arthritis can also cause leg pain but this usually gets worse with movement.[3]

Prevention

Other than preventing the underlying causes, generally no method of preventing RLS has been established or studied. If RLS is due to specific treatable causes (specific medications or treatable conditions), then treatment of those causes may also remove or reduce RLS. Otherwise medical responses focus on treating the condition, either symptomatically or by targeting lifestyle changes and bodily processes capable of modifying its expression or severity.

Treatment

Treatment of restless legs syndrome involves identifying the cause of symptoms when possible. The treatment process is designed to reduce symptoms, including decreasing the number of nights with RLS symptoms, the severity of RLS symptoms and nighttime awakenings. Improving the quality of life is another goal in treatment. This means improving overall quality of life, decreasing daytime sleepiness, and improving the quality of sleep. Pharmacologic treatment involves dopamine agonists or gabapentin enacarbil as first line drugs for daily restless legs syndrome, and opioids for treatment of resistant cases.[52] RLS drug therapy is not curative and has side effects such as nausea, dizziness, hallucinations, orthostatic hypotension, or daytime sleep attacks. An algorithm created by Mayo Clinic researchers provides guidance to the treating physician and patient, including non-pharmacological and pharmacological treatments.[53]

Treatment of RLS should not be considered until possible medical causes are ruled out, especially venous disorders. Secondary RLS may be cured if precipitating medical conditions (anemia, venous disorder) are managed effectively. Secondary conditions causing RLS include iron deficiency, varicose veins, and thyroid problems.

Physical measures

Stretching the leg muscles can bring temporary relief.[9][54] Walking and moving the legs, as the name "restless legs" implies, brings temporary relief. In fact, those with RLS often have an almost uncontrollable need to walk and therefore relieve the symptoms while they are moving. Unfortunately, the symptoms usually return immediately after the moving and walking ceases. A vibratory counter-stimulation device has been found to help some people with primary RLS to improve their sleep.[55]

Non-drug treatments include leg massages, hot baths, heating pads or ice packs applied to the legs, good sleep habits and a vibratory pad at night.[56]

Iron

According to some guidelines, all people with RLS should have their serum ferritin level tested.[53][57] The ferritin level, a measure of the body's iron stores, should be at least 50 µg/L (or ng/mL, an equivalent unit) for those with RLS. Oral iron supplements can increase ferritin levels. For some people, increasing ferritin will eliminate or reduce RLS symptoms; a ferritin level of 50 µg/L is not sufficient for some and increasing the level to 80 µg/L may further reduce symptoms. However, at least 40% of people will not notice any improvement. It is not advised to take oral iron supplements without first having ferritin levels tested, as many people with RLS do not have low ferritin and taking iron when it is not called for is unlikely to offer any therapeutic benefit whilst still able to cause adverse events. All parenteral iron treatments require diagnosis with laboratory tests to avoid iron overload.

Medications

For those whose RLS disrupts or prevents sleep or regular daily activities, medication may be useful. Evidence supports the use of dopamine agonists including: pramipexole, ropinirole, rotigotine, and cabergoline.[58] They reduce symptoms, improve sleep quality and quality of life.[59] Levodopa is also effective.[60] One review found pramipexole to be better than ropinirole.[61]

There are, however, issues with the use of dopamine agonists including augmentation. This is a medical condition where the drug itself causes symptoms to increase in severity and/or occur earlier in the day. Dopamine agonists may also cause rebound, when symptoms increase as the drug wears off. In many cases, the longer dopamine agonists are used the higher the risk of augmentation and rebound as well as the severity of the symptoms. Also, a recent study indicated that dopamine agonists used in restless leg syndrome can lead to an increase in compulsive gambling.[62]

  1. Gabapentin or pregabalin, a non-dopaminergic treatment for moderate to severe primary RLS[63]
  2. Opioids are only indicated in severe cases that do not respond to other measures due to their high rate of side effects.[64]

Benzodiazepines, such as diazepam or clonazepam, are not generally recommended.[65] They however are sometimes still used as a second line agent.[66] Quinine is not recommended due to its risk of serious side effects involving the blood.[67]

Prognosis

RLS symptoms may gradually worsen with age,[51] though more slowly for those with the idiopathic form of RLS than for patients who also have associated medical condition. Nevertheless, current therapies can control the disorder, minimizing symptoms and increasing periods of restful sleep. In addition, some patients have remissions, periods in which symptoms decrease or disappear for days, weeks, or months, although symptoms usually eventually reappear. Being diagnosed with RLS does not indicate or foreshadow another neurological disease.

Epidemiology

RLS affects an estimated 2.5–15% of the American population.[4][68] A minority (around 2.7% of the population) experience daily or severe symptoms.[69] RLS is twice as common in women as in men,[70] and Caucasians are more prone to RLS than people of African descent.[68] RLS occurs in 3% of individuals from the Mediterranean or Middle Eastern region, and in 1–5% of those from the Far East, indicating that different genetic or environmental factors, including diet, may play a role in the prevalence of this syndrome.[68][71]

With age, RLS becomes more common, and RLS diagnosed at an older age runs a more severe course.[54]

RLS is even more common in individuals with iron deficiency, pregnancy, or end-stage kidney disease.[72][73] Poor general health is also linked.[74]

Neurologic conditions linked to RLS include Parkinson's disease, spinal cerebellar atrophy, spinal stenosis, lumbosacral radiculopathy and Charcot–Marie–Tooth disease type 2.[68] Approximately 80–90% of people with RLS also have periodic limb movement disorder (PLMD), which causes slow "jerks" or flexions of the affected body part. These occur during sleep (PLMS = periodic limb movement while sleeping) or while awake (PLMW—periodic limb movement while waking).

The National Sleep Foundation's 1998 Sleep in America poll showed that up to 25 percent of pregnant women developed RLS during the third trimester.[75]

History

The first known medical description of RLS was by Sir Thomas Willis in 1672.[76] Willis emphasized the sleep disruption and limb movements experienced by people with RLS. Initially published in Latin (De Anima Brutorum, 1672) but later translated to English (The London Practice of Physick, 1685), Willis wrote:

“ Wherefore to some, when being abed they betake themselves to sleep, presently in the arms and legs, leapings and contractions on the tendons, and so great a restlessness and tossings of other members ensue, that the diseased are no more able to sleep, than if they were in a place of the greatest torture. ”

The term "fidgets in the legs" has also been used as early as the early nineteenth century.[77]

Subsequently, other descriptions of RLS were published, including those by Francois Boissier de Sauvages (1763), Magnus Huss (1849), Theodur Wittmaack (1861), George Miller Beard (1880), Georges Gilles de la Tourette (1898), Hermann Oppenheim (1923) and Frederick Gerard Allison (1943).[76][78] However, it was not until almost three centuries after Willis, in 1945, that Karl-Axel Ekbom (1907–1977) provided a detailed and comprehensive report of this condition in his doctoral thesis, Restless legs: clinical study of hitherto overlooked disease.[79] Ekbom coined the term "restless legs" and continued work on this disorder throughout his career. He described the essential diagnostic symptoms, differential diagnosis from other conditions, prevalence, relation to anemia, and common occurrence during pregnancy.[80][81]

Ekbom's work was largely ignored until it was rediscovered by Arthur S. Walters and Wayne A. Hening in the 1980s. Subsequent landmark publications include 1995 and 2003 papers, which revised and updated the diagnostic criteria.[9][82] Journal of Parkinsonism and RLS is the first peer-reviewed, online, open access journal dedicated to publishing research about Parkinson's disease and was founded by a Canadian neurologist Dr. Abdul Qayyum Rana.

Controversy

Some doctors express the view that the incidence of restless leg syndrome is exaggerated by manufacturers of drugs used to treat it.[83] Others believe it is an underrecognized and undertreated disorder.[68] Further, GlaxoSmithKline ran advertisements that, while not promoting off-license use of their drug (ropinirole) for treatment of RLS, did link to the Ekbom Support Group website. That website contained statements advocating the use of ropinirole to treat RLS. The ABPI ruled against GSK in this case.[84]

Another point of confusion is that RLS and delusional parasitosis are entirely different conditions that share part of the Wittmaack-Ekbom syndrome eponym, as both syndromes were described by the same person, Karl-Axel Ekbom.[85]

References

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  2. 1 2 3 4 5 "What Is Restless Legs Syndrome?". NHLBI. November 1, 2010. Retrieved 19 August 2016.
  3. 1 2 "What Are the Signs and Symptoms of Restless Legs Syndrome?". NHLBI. November 1, 2010. Retrieved 19 August 2016.
  4. 1 2 3 Ramar, K; Olson, EJ (Aug 15, 2013). "Management of common sleep disorders.". American family physician. 88 (4): 231–8. PMID 23944726.
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  7. 1 2 "How Is Restless Legs Syndrome Treated?". NHLBI. November 1, 2010. Retrieved 19 August 2016.
  8. ↑ "Who Is at Risk for Restless Legs Syndrome?". NHLBI. November 1, 2010. Retrieved 19 August 2016.
  9. 1 2 3 4 Allen, R; Picchietti, D; Hening, WA; Trenkwalder, C; Walters, AS; Montplaisi, J; Restless Legs Syndrome Diagnosis Epidemiology workshop at the National Institutes of Health; International Restless Legs Syndrome Study Group (2003). "Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health". Sleep Medicine. 4 (2): 101–19. doi:10.1016/S1389-9457(03)00010-8. PMID 14592341.
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  25. ↑ Crotti, Francesco Maria; Carai, A.; Carai, M.; Sgaramella, E.; Sias, W. (2005). "Entrapment of crural branches of the common peroneal nerve". Advanced Peripheral Nerve Surgery and Minimal Invasive Spinal Surgery. Acta Neurochirurgica. 97. pp. 69–70. doi:10.1007/3-211-27458-8_15. ISBN 3-211-23368-7.
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  29. ↑ Connor, J.R.; Boyer, P.J.; Menzies, S.L.; Dellinger, B.; Allen, R.P.; Ondo, W.G.; Earley, C.J. (2003). "Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome". Neurology. 61 (3): 304–9. doi:10.1212/01.WNL.0000078887.16593.12. PMID 12913188.
  30. ↑ Desautels, Alex; Turecki, Gustavo; Montplaisir, Jacques; Sequeira, Adolfo; Verner, Andrei; Rouleau, Guy A. (2001). "Identification of a Major Susceptibility Locus for Restless Legs Syndrome on Chromosome 12q". The American Journal of Human Genetics. 69 (6): 1266–70. doi:10.1086/324649.
  31. ↑ Desautels, A.; Turecki, G; Montplaisir, J; Xiong, L; Walters, AS; Ehrenberg, BL; Brisebois, K; Desautels, AK; Gingras, Y; Johnson, WG; Lugaresi, E; Coccagna, G; Picchietti, DL; Lazzarini, A; Rouleau, GA (2005). "Restless Legs Syndrome: Confirmation of Linkage to Chromosome 12q, Genetic Heterogeneity, and Evidence of Complexity". Archives of Neurology. 62 (4): 591–6. doi:10.1001/archneur.62.4.591. PMID 15824258.
  32. ↑ Winkelmann, Juliane; Lichtner, Peter; Pütz, Benno; Trenkwalder, Claudia; Hauk, Stephanie; Meitinger, Thomas; Strom, Tim; Muller-Myhsok, Bertram (2006). "Evidence for further genetic locus heterogeneity and confirmation of RLS-1 in restless legs syndrome". Movement Disorders. 21 (1): 28–33. doi:10.1002/mds.20627. PMID 16124010.
  33. ↑ Bonati, M. T. (2003). "Autosomal dominant restless legs syndrome maps on chromosome 14q". Brain. 126 (6): 1485–92. doi:10.1093/brain/awg137.
  34. ↑ Levchenko, Anastasia; Montplaisir, Jacques-Yves; Dubé, Marie-Pierre; Riviere, Jean-Baptiste; St-Onge, Judith; Turecki, Gustavo; Xiong, Lan; Thibodeau, Pascale; Desautels, Alex; Verlaan, Dominique J.; Rouleau, Guy A. (2004). "The 14q restless legs syndrome locus in the French Canadian population". Annals of Neurology. 55 (6): 887–91. doi:10.1002/ana.20140. PMID 15174026.
  35. ↑ Kemlink, David; Polo, Olli; Montagna, Pasquale; Provini, Federica; Stiasny-Kolster, Karin; Oertel, Wolfgang; De Weerd, Al; Nevsimalova, Sona; Sonka, Karel; Högl, Birgit; Frauscher, Birgit; Poewe, Werner; Trenkwalder, Claudia; Pramstaller, Peter P.; Ferini-Strambi, Luigi; Zucconi, Marco; Konofal, Eric; Arnulf, Isabelle; Hadjigeorgiou, Georgios M.; Happe, Svenja; Klein, Christine; Hiller, Anja; Lichtner, Peter; Meitinger, Thomas; Müller-Myshok, Betram; Winkelmann, Juliane (2007). "Family-based association study of the restless legs syndrome loci 2 and 3 in a European population". Movement Disorders. 22 (2): 207–12. doi:10.1002/mds.21254. PMID 17133505.
  36. ↑ Chen, Shenghan; Ondo, William G.; Rao, Shaoqi; Li, Lin; Chen, Qiuyun; Wang, Qing (2004). "Genomewide Linkage Scan Identifies a Novel Susceptibility Locus for Restless Legs Syndrome on Chromosome 9p". The American Journal of Human Genetics. 74 (5): 876–885. doi:10.1086/420772.
  37. ↑ Liebetanz, K. M.; Winkelmann, J; Trenkwalder, C; Pütz, B; Dichgans, M; Gasser, T; Müller-Myhsok, B (2006). "RLS3: Fine-mapping of an autosomal dominant locus in a family with intrafamilial heterogeneity". Neurology. 67 (2): 320–321. doi:10.1212/01.wnl.0000224886.65213.b5. PMID 16864828.
  38. ↑ Lohmann-Hedrich, K.; Neumann, A.; Kleensang, A.; Lohnau, T.; Muhle, H.; Djarmati, A.; König, I. R.; Pramstaller, P. P.; Schwinger, E.; Kramer, P. L.; Ziegler, A.; Stephani, U.; Klein, C. (2008). "Evidence for linkage of restless legs syndrome to chromosome 9p: Are there two distinct loci?". Neurology. 70 (9): 686–694. doi:10.1212/01.wnl.0000282760.07650.ba. PMID 18032746.
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  40. ↑ Pichler, Irene; Marroni, Fabio; Beu Volpato, Claudia; Gusella, James F.; Klein, Christine; Casari, Giorgio; De Grandi, Alessandro; Pramstaller, Peter P. (2006). "Linkage Analysis Identifies a Novel Locus for Restless Legs Syndrome on Chromosome 2q in a South Tyrolean Population Isolate". The American Journal of Human Genetics. 79 (4): 716–23. doi:10.1086/507875.
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